Myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal hematologic disorders characterized by ineffective hematopoiesis and dysplasia. In MDS, genomic abnormalities accumulate in a hematopoietic stem cell leading to peripheral cytopenias of varying degrees of severity, as a consequence of multilineage differentiation impairment, and, in the early phases, bone marrow (BM) apoptosis. Morbidity and mortality in the disease results from cytopenias or transformation to acute myeloid leukemia, which may both lead to serious infectious diseases, anemia or hemorrhage caused by dysfunction and reduction of blood cells.
Cytopenia (low blood cell count) results from a high rate of apoptosis within the bone marrow environment and consequent lack of release of cells into the peripheral blood circulation (Kitamura et al, 2014; Kerbauy et al, 2007). Diagnosing MDS can be challenging, especially during early stages when a patient's symptoms include cytopenia without an increase in blasts. There are numerous reactive processes that cause cytopenia including drug reaction, nutritional or hormonal deficiencies, and autoimmune diseases or chronic infection.
The major criteria for diagnosing MDS are the presence of peripheral cytopenia and dysplasia. However, evaluating dysplasia is subjective and can be difficult without bone marrow biopsy. Yet, proper and early diagnosis is very important for treating and managing progression of MDS because a chance for remission is much higher if MDS is detected prior to the stage where it has progressed to leukemia.
In patients presenting with cytopenia, MDS should be considered, but confirmation of diagnosis requires bone marrow biopsy and morphologic and cytogenetic evaluation. The diagnosis of MDS currently requires a multidisciplinary approach involving hematologic, morphologic and cytogenetic analyses, and may be difficult to render due to the fact that only about half of patients demonstrate cytogenetic abnormalities. The choice of therapies used to treat MDS heavily depends on disease severity and the risk of progression to more advanced disease. The ability to accurately formulate prognosis is therefore an essential component of patient care.
Current prognostic scoring systems consider karyotypic abnormalities and certain clinical features to stratify MDS patients into risk groups. Some karyotypic abnormalities help establish prognosis and can be associated with a specific clinical phenotype. However, more than half of MDS patients have a normal karyotype, and patients with identical chromosomal abnormalities remain clinically heterogeneous. It is extremely difficult to rely on subjective morphologic features to confirm the diagnosis of MDS, when the karyotype is normal and blasts are not increased.
Molecular evaluation can be helpful in providing objective means for the demonstration of abnormal mutant clone and confirmation of the diagnosis of MDS (Itzykson et al, 2013; Bejar et al, 2011; Haferlach et al, 2014; Thol et al, 2012; Malcovati et al, 2014). Due to the cytopenia in peripheral blood, molecular studies of DNA extracted from peripheral blood cells may not identify abnormal clones with adequate sensitivity; hence samples obtained from bone marrow are considered more reliable for detecting molecular abnormalities and confirming diagnosis of MDS.
The detected abnormalities have clinical implication on prognosis and determining therapy. In addition, it is important to test patients by using sensitive methods that are capable of detecting the presence of subclones that may dictate the overall prognosis (Bejar et al, 2013). MDS is a disease of excessive apoptosis in bone marrow, DNA resulting from this apoptosis is abundant in circulation because hematopoietic cells are immersed in blood; these cells pour their contents during apoptosis or necrosis through blood in the form of apoptotic bodies, exosomes, microvessels, or DNA-protein complexes (Giles et al, 2007).
There is a need for a reliable accurate method to diagnose MDS, especially at an early stage. Such methods will be helpful for identifying a patient who will benefit from a treatment for MDS. Further, as current methods rely on bone marrow biopsy which is a highly invasive and painful procedure, a significant advancement in treatment and diagnostics can be achieved with a procedure which does not require obtaining a sample from bone marrow.